Process for preparation of imidazolyl compounds

ABSTRACT

A method for preparing an imidazolyl compound corresponding to the formula (I)  
                 
 
     by reacting a compound corresponding to formula (II)  
                 
 
     with a compound corresponding to formula (III)  
                 
 
     and then reacting the product with a compound corresponding to formula (IV)

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a process for the preparation ofimidazolyl compounds.

[0002]1,2,3,9-Tetrahydro-9-methyl-3-[2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one(ondansetron) is known from EP191562 and U.S. Pat. No. 4,695,578. Thesepatent publications describe a general class of compounds includingondansetron and homologous compounds, their preparation and their usesas potent selective antagonists at “neuronal” 5-hydroxytryptaminereceptors and in the treatment of migraine and psychotic disorders.

[0003](10R)-5,6,9,10-Tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-pyrido[3,2,1-jk]-carbazol-11(8H)-one(cilansetron) (also known as(R)-(−)-4,5,6,8,9,10-hexahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-11H-pyrido-[3,2,1-jk]-carbazol-11-one)is known from U.S. Pat. No. 4,939,136 (=EP 297,651), from U.S. Pat. No.5,438,068 (=EP 601,345) and from U.S. Pat. No. 5,663,343 (=EP 768,309).The first patent describes a general class of compounds, includingcilansetron and homologous compounds, their preparation and their use as5-HT antagonists. The second patent describes the use of selectedcompounds of this type for the treatment of certain diseases, and thethird patent describes the preparation of enantiomerically purecompounds and their hydrochloride monohydrate.

[0004] It is a common feature of the above compounds that they contain asubstituted imidazolyl group attached via a methylene bridge to theα-position relative to the keto group of the carbazole system. Severalpossibilities for the synthesis of these compounds are described in theaforementioned patent publications. A common feature in these synthesesis that the substituted imidazolyl group is introduced by means of aMannich reaction, followed by a deamination to yield an intermediateexomethylene compound which is reacted with the substituted imidazolylgroup (see scheme 1 for an example).

[0005] A drawback of this synthesis route is that the yield in thissequence of reaction steps is rather low. In U.S. Pat. No. 4,695,578 thefirst step, which is normally gives the lowest yield, is not described,and the second step (Example 7 of U.S. Pat. No. 4,695,578) gives a yieldof 68%. In U.S. Pat. No. 4,939,136 the first step (Example 1c of U.S.Pat. No. 4,939,136) has a yield of 53% and the second step (Example 1dof U.S. Pat. No. 4,939,136) a yield of 87%. During scale-up it appearedthat this route gives rise to the formation of a considerable amount oftar-like by-products.

SUMMARY OF THE INVENTION

[0006] It is an object of the present invention to provide analternative process for preparing imidazolyl-compounds.

[0007] Another object of the process is to provide a process forpreparing imidazolyl-compounds which is highly cost effective.

[0008] A further object of the invention is to provide a process forpreparing imidazolyl-compounds which produces relatively high yields ofthe desired product.

[0009] It is also an object of the invention to provide a process forpreparing imidazolyl-compounds with short reaction times compared withprior art processes.

[0010] An additional object of the invention is to provide a process forpreparing imidazolyl-compounds which exhibits fewer side reactions.

[0011] Yet another object of the invention is to provide a process forpreparing imidazolyl-compounds which yields final product of higherquality.

[0012] A still further object of the invention is to provide a processfor preparing imidazolyl-compounds which uses non-diluted reactionconditions and an environmentally acceptable solvent.

[0013] These and other objects are achieved in accordance with thepresent invention by providing a process for preparing an imidazolylcompound as described and claimed hereinafter.

[0014] It has surprisingly been found that this type of imidazolylcompound can easily be prepared using a substituted oxazolidine compoundfor the introduction of the methylene bridge. Thus, the presentinvention relates to a method for preparation of an imidazolyl compoundcorresponding to the formula (I)

[0015] wherein:

[0016] R_(a) and R_(b) are each individually selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆) alkoxyalkyl, and optionallysubstituted aryl and heteroaryl; or

[0017] R_(a) and R_(b) together form a further homocyclic orheterocyclic system comprising one or more rings;

[0018] R_(a′) and R_(b′) are each hydrogen or together form acarbon-carbon double bond, said carbon-carbon double bond optionallybeing part of an aromatic system;

[0019] R_(c) is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxyalkyl or halogen;

[0020] R_(d) is hydrogen or (C₁-C₄)alkyl;

[0021] R_(e) is hydrogen or (C₁-C4)alkyl;

[0022] m is 1 or 2; and

[0023] R₁ is hydrogen or (C₁-C₄)alkyl; or an acid addition salt thereof;said method comprising

[0024] a) reacting a compound corresponding to the formula (II)

[0025] wherein R_(a), R_(a′), R_(b) and R_(b′) have the meanings definedabove; with a compound of the formula (III)

[0026] wherein:

[0027] R is a hydrogen, a (C₁-C₄)alkyl group optionally substituted witha hydroxygroup, or an optionally substituted aryl group, and

[0028] R′, R″, R′″ and R″″ are each individually a hydrogen or a(C₁-C₄)alkyl group; and then

[0029] b) reacting a product of step a) with a compound corresponding tothe formula (IV)

[0030] wherein R₁, R_(d) and R_(e) have the meanings defined above; and

[0031] c) optionally reacting a product of step b) with an acid toobtain an acid addition salt.

[0032] Alkyl groups of the present invention include straight-chained,branched and cyclic alkyl radicals containing up to 6 carbon atoms.Suitable alkyl groups may be saturated or unsaturated. Further, an alkylgroup may also be substituted one or more times with substituentsselected from the group consisting of aryl, halo, hydroxy, cyano,monoalkyl amino and dialkyl amino.

[0033] Aryl groups of the present invention include aryl radicals whichmay contain up to 6 hetero atoms. An aryl group may also be optionallysubstituted one or more times with a substituent selected from the groupconsisting of aryl, (C₁-C₆)alkyl, halo, hydroxy, cyano, monoalkyl aminoand dialkyl amino, and it may also be fused with another aryl group orwith one or more cycloalkyl rings. Suitable aryl groups include, e.g.,phenyl, naphthyl, tolyl, imidazolyl, pyridyl, pyrroyl, thienyl,pyrimidyl, thiazolyl and furyl groups.

[0034] As used herein, the term “homocyclic system” means a systemcontaining at least one saturated or unsaturated cyclic group containingonly carbon atoms and hydrogen atoms. The term “heterocyclic system” asused herein means a system containing at least one saturated orunsaturated cyclic group which includes one or more heteroatoms such asN, O or S. Both the homocyclic and heterocyclic systems may optionallybe substituted with one or more substituents selected from the groupconsisting of alkyl, aryl, cyano, halogen, hydroxyl, monoalkylamino anddialkylamino groups.

[0035] In one preferred embodiment of the invention R_(c) is hydrogen or(C₁-C₆)alkyl, R_(d) is hydrogen or (C₁-C₄)alkyl; R_(e) is hydrogen or(C₁-C₄)alkyl; and R₁ is hydrogen, methyl or ethyl.

[0036] The reaction according to the invention is especially useful forthe preparation of compounds corresponding to the formula (Ia)

[0037] wherein:

[0038] m is 1 or 2;

[0039] R₁ is hydrogen, methyl or ethyl;

[0040] R₅ is a (C₁-C₄) alkyl; and

[0041] R₆ is a hydrogen or a (C₁-C₄)alkyl, or

[0042] R₅ and R₆ together with the intermediate atoms form a 5, 6, or 7membered ring, optionally substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, (C₁-C₄)alkyl,(C₁-C₄)alkoxyalkyl and (C₁-C₄)alkoxy.

[0043] In this case the starting compound is a compound corresponding tothe formula (IIa)

[0044] This compound is further referred to as a carbazolone compound.

[0045] Preferred compounds corresponding to formula Ia are the compoundin which m=1 and R₅ and R₆ together with the intermediate atoms form a6-membered ring and the compound in which m=1, R₅ is methyl and R₆ ishydrogen. For the first compound the yield for the process starting with5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one and3-oxazolidineethanol is 77% (see Example 2) compared with the overallyield of 46% in the process according to U.S. Pat. No. 4,939,136(Examples Ic and Id). Higher yields may be obtained at a productionscale.

[0046] In the substituted oxazolidine, preferably one of R′ and R″ andone of R′″ and R″″ is hydrogen, inasmuch as an oxazolidine which isdisubstituted on the same carbon atom, such as 4,4-dimethyloxazolidine,gives a lower yield in the reaction. Preferred oxazolidines are3-oxazolidineethanol and 3-ethyl-oxazolidine. The most preferredoxazolidine is 3-oxazolidineethanol.

[0047] The reaction is carried out in an acidic medium, and the degreeof acidity required depends on the activation of the system that has toreact. In the case of carbazolone systems, the medium should be highlyacidic. Examples of suitable acids for use in such a case includemethanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonicacid and gaseous HCl in an alcoholic medium.

[0048] In order to obtain a high yield, the reaction solution shouldcontain only a low amount of water. The amount of water shouldpreferably be below 0.6% (V/V), more preferably below 0.3% V/V, and mostpreferably below 0.1% V/V.

[0049] The optimal reaction temperature is dependent on the startingmaterial and the solvent and differs for the two reaction steps. Thefirst step of the reaction can be performed at temperatures between 40°C. and 110° C. For the carbazolone systems the preferred reactiontemperature in the first step is between 50° C. and 90° C., and the mostpreferred temperature is about 70° C. The second step can generally becarried out at temperatures between 100° C. and 140° C. For thecarbazolone systems the preferred reaction temperature in the secondstep is between 110° C. and 130° C., and the most preferred temperatureis about 120° C.

[0050] The reaction can be performed in different solvents such asdipolar aprotic solvents like dimethylformamide (DMF) or in alcohols.Preferred solvents are C₄-C₇ alcohols. The choice of solvent may dependon the desired reaction temperature. Examples of suitable alcoholsinclude 1-butanol, 1-hexanol and isoamyl alcohol. A preferred alcohol is1-butanol. Also suitable are mixtures of aromatic hydrocarbons andalcohols, such as mixtures of toluene and an alcohol or mixtures ofmonochlorobenzene and an alcohol. A preferred mixture is a mixture ofmonochlorobenzene and methanol. When a solvent mixture is used, thelower boiling solvent can be distilled off before the second step inorder to attain higher reflux temperatures of the solvent system in thesecond step.

[0051] The ratio of the solvent volume to the amount of reactants in themixture can be varied over a relatively broad range and depends on thesolubility of the reactants. In general the ratio of the amount ofsolvent to the amount of reactants can typically range from about 1:1 to15:1, where the ratio is expressed as the volume in ml of the solventrelative to the weight in grams of the reactants in the solvent.Preferably the ratio is about 1:1 to about 10:1. In the case of thecarbazolone systems, the preferred ratio of the volume of solvent to theweight of reactants is about 4:1.

[0052] The products obtained can be crystallized from differentsolvents. Examples of solvents for the cyrstallisation of free basesinclude aromatic hydrocarbons such as toluene. The hydrochloric acidsalts can be crystallized, e.g., from alcoholic solvents such asisopropanol or 1-butanol.

[0053] The following examples are only intended to further illustratethe invention in more detail, and therefore these examples are notdeemed to restrict the scope of the invention in any way.

EXAMPLE 1 Materials and Methods

[0054] 5,6,9,10-Tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one wasproduced as described in published European patent application no. EP375,045. 3,4-Dihydro-1(2H)-naphthalenone was obtained from a commercialsource. 1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one was produced asdescribed in U.S. Pat., No. 3,892,766 from Warner-Lambert Company andElz, S. and Heil, W., Bioorganic & Medicinal Chemistry Letters 1995, 5,667-672. Methanesulfonic acid was obtained from a commercial source.

[0055] NMR spectra were measured on a Varian VXR 200 and MS spectra on aFinnigan TSQ 7000. HPLC analyses were performed on a HP1050 system witha Separations 757 detector (250 nm) and a Separations Marathon XT columnoven at 35° C. The column used was a Zorbax XDB C8 colomn 15×0.3 cm. Theeluent was prepared as follows: mix 2 liters water, 2 ml triethylamineand 5 ml 25% ammonia, buffer the resulting mixture at pH=4 with formicacid, and add 0.5 liter of acetonitrile. The flow was 1 ml/min.

EXAMPLE 1a Preparation of Oxazolidines

[0056] 3-Oxazolidineethanol was prepared as follows:

[0057] Equimolar amounts of diethanolamine and paraformaldehyde in1-butanol were heated to 70° C. After 1 hour reaction time the resultingwater was removed by azeotropic distillation with 1-butanol.

[0058] 3-Ethyl-oxazolidine was prepared according to Heany, H. et al.,Tetrahedron 1997, 53, 14381-96.

[0059] 4,4-Dimethyl-oxazolidine is commercially available and waspurchased as a 75% w/w solution in water. The 4,4-dimethyl-oxazolidinewas extracted from the water layer by washing withdichloromethane/saturated NaCl-solution. The dichloromethane layer wasdried over anhydrous sodium sulfate and subsequently evaporated.

EXAMPLE 2 Reaction of5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one with3-oxazolidineethanol

[0060] 5,6,9,10-Tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (25.00g≡111.0 mmole) and methanesulfonic acid (17.06 g≡177.5 mmole) in1-butanol (100 ml) were heated to 70° C. In 3 minutes a solution of3-oxazolidineethanol (19.49 g≡166.4 mmole) in 1-butanol (39 ml) wasadded. After 50 minutes at 80° C. 2-methylimidazole (45.55 g≡554.8mmole) and 1-butanol (10 ml) were added. After 1.5 hours at 120° C. thereaction mixture was partly evaporated till 30 ml of 1-butanol remained.

[0061] At 70° C., 75 ml of toluene and 50 ml of water were added to theresidue. The layers were separated. The water layer was extracted with75 ml of toluene. The combined toluene layers were washed three timeswith 100 ml of water.

[0062] The organic layer was evaporated to dryness, and subsequently 125ml of 1-butanol was added. To the resulting solution 12.5 ml of 36% m/mhydrochloric acid was added. After stirring for 2 hours at roomtemperature, the resulting solid was filtered out and washed with1-butanol and MTBE. Yield after drying: 30.40 g (77.0%)5,6,9,10-tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-pyrido[3,2,1-jk]carbazol-11(8H)-onehydrochloride (77.0%). HPLC: ≧95%. ¹H NMR [200 MHz, DMSO-d⁶:CDCl₃ 4:1] δ1.97(1H,m), 2.18 (3H,m), 2.68(3H,s), 2.95(2H,t), 3.00(1H,dd),3.12(2H,m), 4.13(2H,m), 4.29(1H,dd), 4.66(1H,dd), 6.97(1H,d),7.09(1H,t), 7.55(1H,d), 7.68(1H,d) and 7.71(1H,d). MS [ESI] MH⁺=320.

EXAMPLE 3 Reaction of5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one with4,4-dimethyl-oxazolidine

[0063] 5,6,9,10-Tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (20.00g≡88.8 mmole) and methanesulfonic acid (13.65 g≡142.0 mmole) in1-butanol (60 ml) were heated to 70° C. In 2 minutes4,4-dimethyl-oxazolidine (13.47 g≡133.2 mmole) in 1-butanol (10 ml) wasadded.

[0064] After 50 minutes at 80° C. 2-methylimidazole (36.45 g≡444.0mmole) and butanol (10 ml) were added. After 2 hours at 120° C. thereaction mixture was partly evaporated till 20 ml of 1-butanol remained.

[0065] At 70° C., 60 ml of toluene and 40 ml of water were added to theresidue. The layers were separated. The water layer was extracted with60 ml of toluene. The combined toluene layers were washed three timeswith 80 ml of water.

[0066] The organic layer was evaporated to dryness, and subsequently 100ml of 1-butanol was added. To the resulting solution 10.0 ml of 36% m/mhydrochloric acid was added. After stirring for 2 hours at roomtemperature the resulting solid was filtered out and washed with1-butanol and MTBE. Yield after drying: 12.38 g 5,6,9,10-tettrahvdro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-pyrido[3,2,1-jk]carbazol-11(8H)-onehydrochloride (39.2%). HPLC: ≧95%. ¹H NMR and MS: see Example 2. Themother liquor contained 3.45 g (10.9%) of product.

EXAMPLE 4 Reaction of5,6,9,10-tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one with3-ethyl-oxazolidine

[0067] 5,6,9,10-Tetrahydro-4H-pyrido[3,2,1-jk]carbazol-11(8H)-one (20.00g≡88.8 mmole) and methanesulfonic acid (13.65 g≡142.0 mmole) in1-butanol (60 ml) were heated to 70° C. In 2 minutes 3-ethyl-oxazolidine(13.46 g≡133.2 mmole) in 1-butanol (10 ml) was added.

[0068] After 50 minutes at 80° C. 2-methylimidazole (36.45 g≡444.0mmole) and 1-butanol (10 ml) were added. After 2 hours at 120° C. thereaction mixture was partly evaporated till 20 ml of 1-butanol remained.

[0069] At 70° C., 60 ml of toluene and 40 ml of water were added to theresidue. The layers were separated. The water layer was extracted with60 ml of toluene. The combined toluene layers were washed three timeswith 80 ml of water.

[0070] The organic layer was evaporated to dryness, and subsequently 100ml of 1-butanol was added. To the resulting solution 10.0 ml of 36% m/mhydrochloric acid was added. After stirring for 2 hours at roomtemperature the resulting solid was filtered out and washed with1-butanol and MTBE. Yield after drying: 22.10 g (70.0%)5,6,9,10-tetrahydro-10-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-pyrido[3,2,1-jk]carbazol-11(8H)-onehydrochloride (70.0%). HPLC: ≧95%. ¹H NMR and MS: see Example 2.

EXAMPLE 5 Reaction of 3,4-dihydro-1(2H)-naphthalenone with3-oxazolidineethanol

[0071] 3,4-Dihydro-1(2H)-naphthalenone (12.98 g≡88.8 mmole) andmethanesulfonic acid (13.65 g≡142.0 mmole) in 1-butanol (60 ml) wereheated to 50° C. In 2 minutes a solution was added of3-oxazolidineethanol (15.59 g≡133.1 mmole) in 1-butanol (14 ml).

[0072] After 50 minutes at 80° C. 2-methylimidazole (36.45 g≡444.0mmole) and 1-butanol (10 ml) were added. After 2 hours at 120° C. thereaction mixture was partly evaporated till 20 ml of 1-butanol remained.

[0073] At 70° C., 60 ml of toluene and 40 ml of water were added to theresidue. The layers were separated. The water layer was extracted with60 ml of toluene. The combined toluene layers were washed three timeswith 80 ml of water.

[0074] The organic layer was evaporated to dryness and subsequently 100ml of 1-butanol was added. To the resulting solution 10.0 ml of 36% m/mhydrochloric acid was added. The resulting solution was evaporated untilan end volume of 60 ml was reached. After stirring for 2 hours at roomtemperature the resulting solid was filtered out and washed with1-butanol and MTBE. Yield after drying: 15.28 g (62.2%)3,4-dihydro-2-[(2-methyl-1H-imidazol-1-yl)methyl]-1(2H)-naphthalenonehydrochloride. HPLC: ≧95%. ¹H NMR[200 MHz, DMSO-d⁶:CDCl₃ 4:1] δ 2.00(2H,m), 2.73 (3H,s), 3.20 (3H,m), 4.27 (1H,dd), 4.68 (1H,dd), 7.35(2H,t), 7.55 (2H,m), 7.70 (1H,d) and 7.90 (1H,d). MS [ESI] MH⁺=241. Themother liquor contained 3.28 g (13.3%) of product.

EXAMPLE 6 Reaction of 3,4-dihydro-1(2H)-naphthalenone with4,4-dimethyl-oxazolidine

[0075] 3,4-Dihydro-1(2H)-naphthalenone (12.98 g≡88.8 mmole) andmethanesulfonic acid (13.65 g≡142.0 mmole) in 1-butanol (60 ml) wereheated to 70° C. In 2 minutes 4,4-dimethyl-oxazolidine (13.46 g≡133.1mmole) in 1-butanol (10 ml) was added. After 50 minutes at 80° C.2-methylimidazole (36.45 g≡444.0 mmole) and 1-butanol (10 ml) wereadded. After 2 hours at 120° C. the reaction mixture was partlyevaporated till 20 ml of 1-butanol remained.

[0076] At 70° C., 60 ml of toluene and 40 ml of water were added to theresidue. The layers were separated. The water layer was extracted with60 ml of toluene. The combined toluene layers were washed three timeswith 80 ml of water.

[0077] The organic layer was evaporated to dryness, and subsequently 100ml of 1-butanol was added. To the resulting solution 10.0 ml of 36% m/mhydrochloric acid was added. The resulting solution was evaporated untilan end volume of 50 ml was reached. After stirring for 2 hours at 0° C.,the resulting solid was filtered out and washed with 1-butanol and MTBE.Yield after drying: 14.13 g (57.5%)3,4-dihydro-2-[(2-methyl-1H-imidazol-1-yl)methyl]-1(2H)-naphthalenonehydrochloride. HPLC: ≧95%. ¹H NMR and MS: see Example 5. The motherliquor contained 2.33 g (9.5%) of product.

EXAMPLE 7 Reaction of 3,4-dihydro-1(2H)-naphthalenone with3-ethyl-oxazolidine

[0078] 3,4-Dihydro-1(2H)-naphthalenone (12.98 g≡88.8 mmole) andmethanesulfonic acid (13.65 g≡142.0 mmole) in 1-butanol (60 ml) wereheated to 50° C. In 2 minutes 3-ethyl-oxazolidine (13.46 g≡133.1 mmole)in 1-butanol (10 ml) was added. After 50 minutes at 80° C.2-methylimidazole (36.45 g≡444.0 mmole) and 1-butanol (10 ml) wereadded. After 2 hours at 120° C. the reaction mixture was partlyevaporated till 20 ml of 1-butanol remained.

[0079] At 70° C., 60 ml of toluene and 40 ml of water were added to theresidue. The layers were separated. The water layer was extracted with60 ml of toluene. The combined toluene layers were washed three timeswith 80 ml of water.

[0080] The organic layer was evaporated to dryness, and subsequently 100ml of 1-butanol was added. To the resulting solution 10.0 ml of 36% m/mhydrochloric acid was added. The resulting solution was evaporated untilan end volume of 50 ml was reached. After stirring for 2 hours at 0° C.the resulting solid was filtered out and washed with 1-butanol and MTBE.Yield after drying: 17.30 g3,4-dihydro-2-[(2-methyl-1H-imidazol-1-yl)methyl]-1(2H)-naphthalenonehydrochloride (70.4%). HPLC: ≧95%. ¹H NMR and MS: see Example 5.

EXAMPLE 8 Reaction of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with3-oxazolidineethanol

[0081] 1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one (13.26 g≡66.5mmole) and methanesulfonic acid (10.23 g≡106.4 mmole) in 1-butanol (45ml) were heated to 90° C. In 2 minutes 11.68 g (99.8 mmole) of3-oxazolidineethanol in 1-butanol (11 ml) was added.

[0082] After 50 minutes at 80° C. 2-methylimidazole (27.32 g≡332.5mmole) and 1-butanol (8 ml) were added. After 2 hours at 120° C. 180 mlof toluene and 120 ml of water were added at 80° C. The layers wereseparated. The water layer was extracted with 180 ml of toluene and 60ml of 1-butanol. The combined organic layers were washed twice with 240ml of water. The organic layer was evaporated to dryness. 150 ml of1-butanol and 10 ml of 36% m/m hydrochloric acid were added to theresidue. At 0° C. crystallization soon occurred. After 1 hour at 0° C.the resulting crystals were filtered out, washed with 1-butanol and MTBEand subsequently dried: 15.39 g (70.1%) of1,2,3,9-Tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride were isolated. HPLC: ≧95%. ¹H NMR [200 MHz, DMSO-d⁶:CDCl₃4:1] δ 2.00 (1H,m), 2.20 (1H,m), 3.69 (3H,s), 3.09 (3H,m), 3.75 (3H,s),4.30 (1H,dd), 4.67 (1H,dd), 7.23 (2H,m), 7.53 (2H,m), 7.69 (1H,d), 8.01(1H, d). MS [ESI] MH⁺=294. The mother liquor contained 3.19 g (14.5%) ofproduct.

EXAMPLE 9 Reaction of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with4,4-dimethyl-oxazolidine

[0083] 1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one (13.26 g≡66.5mmole) and methane-sulfonic acid (10.23 g≡106.4 mmole) in 1-butanol (45ml) were heated to 90° C. In 2 minutes 4,4-dimethyl-oxazolidine (10.09g≡99.9 mmole) in 1-butanol (8 ml) was added.

[0084] After 50 minutes at 80° C. 2-methylimidazole (27.32 g≡332.5mmole) and 1-butanol (8 ml) were added. After 2 hours at 120° C. 180 mlof toluene and 120 ml of water were added at 80° C. The layers wereseparated. The water layer was extracted with 180 ml of toluene and 60ml of 1-butanol. The combined organic layers were washed twice with 240ml of water. The organic layer was evaporated to dryness. 150 ml of1-butanol and 10 ml of 36% m/m hydrochloric acid were added to theresidue. At 0° C. crystallization soon occurred. After 1 hour at 0° C.the resulting crystals were filtered out, washed with 1-butanol and MTBEand subsequently dried. 10.02 g (45.7%) of1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride were obtained. The mother liquor contained 2.70 g (12.3%)of product. HPLC: ≧95%. NMR and MS: see Example 8.

EXAMPLE 10 Reaction of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-onewith 3-ethyl-oxazolidine

[0085] 1,2,3,9-Tetrahydro-9-methyl-4H-carbazol-4-one (13.26 g≡66.5mmole) and methane-sulfonic acid (10.23 g≡106.4 mmole) in 1-butanol (45ml) were heated to 90° C. In 2 minutes 3-ethyl-oxazolidine (10.09 g≡99.9mmole) in 1-butanol (8 ml) was added.

[0086] After 50 minutes at 80° C. 2-methylimidazole (27.32 g≡332.5mmole) and 1-butanol (8 ml) were added. After 2 hours at 120° C. 180 mlof toluene and 120 ml of water were added at 80° C. The layers wereseparated. The water layer was extracted with 180 ml of toluene and 60ml of 1-butanol. The combined organic layers were washed twice with 240ml of water. The organic layer was evaporated to dryness. 150 ml of1-butanol and 10 ml of 36% m/m hydrochloric acid were added to theresidue. At 0° C. crystallization soon occurred. After 1 hour at 0° C.the resulting crystals were filtered out, washed with 1-butanol and MTBEand subsequently dried. 15.67 g (71.4%) of1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-onehydrochloride were isolated. HPLC: ≧95%. NMR and MS: see Example 8. Themother liquor contained 2.06 g (9.4%) of product.

[0087] The foregoing description and examples have been set forth merelyto illustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations withinthe scope of the appended claims and equivalents thereof.

What is claimed is:
 1. A method for preparing an imidazolyl compoundcorresponding to formula (I)

wherein: R_(a) and R_(b) are each individually selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)alkoxyalkyl, and optionallysubstituted aryl and heteroaryl; or R_(a) and R_(b) together form afurther homocyclic or heterocyclic system comprising one or more rings;R_(a′) and R_(b′) are each hydrogen or together form a carbon-carbondouble bond, said carbon-carbon double bond optionally being part of anaromatic system; R_(c) is hydrogen, (C₁-C₆)alkyl, (C₁-C₆)alkoxy,(C₁-C₆)alkoxyalkyl or halogen; R_(d) is hydrogen or (C₁-C₄)alkyl; R_(e)is hydrogen or (C₁-C₄)alkyl; m is 1 or 2; and R₁ is hydrogen or(C₁-C₄)alkyl; or an acid addition salt thereof; said method comprising:a) reacting a compound corresponding to formula (II)

wherein R_(a), R_(a′), R_(b) and R_(b′) have the meanings defined above;with a compound corresponding to formula (III)

wherein: R is a hydrogen, a (C₁-C₄)alkyl optionally substituted with ahydroxyl group, or an optionally substituted aryl group, and R′, R″, R′″and R″″ are each individually a hydrogen or a (C₁-C₄)alkyl group; andthen b) reacting a product of step a) with a compound corresponding toformula (IV)

wherein R₁, R_(d) and R_(e) have the meanings defined above; and c)optionally reacting a product of step b) with an acid to obtain an acidaddition salt.
 2. A method according to claim 1, wherein R_(c) ishydrogen or (C₁-C₆)alkyl, and R₁ is hydrogen, methyl or ethyl.
 3. Amethod according to claim 1, for preparing an imidazolyl compoundcorresponding to the formula (Ia)

wherein: m is 1 or 2; R₁ is hydrogen, methyl or ethyl; R₅ is(C₁-C₄)alkyl, and R₆ is hydrogen or (C₁-C₄)alkyl, or R₅ and R₆ togetherwith the intermediate atoms form a 5, 6, or 7 member ring, optionallysubstituted with one or two substituents selected from the groupconsisting of halogen, hydroxyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxyalkyl and(C₁-C₄)alkoxy; or a pharmaceutically acceptable acid addition saltthereof; said method comprising: a) reacting a compound corresponding tothe formula (IIa)

wherein R₅, R₆ and m have the meanings defined above; with a compoundcorresponding to the formula (III)

and then b) reacting a product of a) with a compound corresponding tothe formula (IVa)

wherein R1 has the meaning given above.
 4. A method according to claim1, wherein R is a 2-hydroxyethyl group, and R′, R″, R′″ and R″″ are eachhydrogen.
 5. A method according to claim 1, wherein m=1, and R₅ and R₆together with the intermediate atoms form a 6-member rind.
 6. A methodaccording to claim 1, wherein m=1; R₅ is methyl, and R₆ is hydrogen. 7.A method according to claim 1, wherein the reaction is carried out in analcoholic solvent.
 8. A method according to claim 7, wherein thealcoholic solvent is 1-butanol.
 9. A method according to claim 1,wherein the reaction is carried out in a mixture of an alcoholic solventand an aromatic hydrocarbon
 10. A method according to claim 9, whereinsaid mixture is a mixture of methanol and chlorobenzene.